Heterogeneity of blood-brain barrier changes in multiple sclerosis: An MRI study with gadolinium-DTPA enhancement A.G. Kermode, MRCP; P.S. Tofts, PhD; A.J. Thompson, MRCP; D.G. MacManus, DCR P. Rudge, FRCP; B.E. Kendall, FRCR D.P.E. Kingsley, FRCR I.F. Moseley, FRCR, E.P.G.H. du Boulay, FRCR, and W.I. McDonald, FRCP Article abstract-We performed 15 dynamic gadolinium-DTPA (Gd-DTPA)-enhanced MRI studies in 8 patients with relapsing and remitting multiple sclerosis; 7 were follow-up studies. We measured the time course of enhancement in 102 enhancing lesions for up to 384 minutes, with rest breaks. Immediate postcontrast MRIs demonstrated many different patterns of enhancement. We observed both uniformly enhancing and ring enhancing lesions. The enhancing regions were often less extensive than the corresponding high signal on T,-weighted images. Three lesions were seen with Gd-DTPA but not on unenhanced scans; 1was seen on unenhanced scans 10 days later, suggesting that blood-brain barrier disturbance may precede other MRI signs of MS lesions. Three months later, some high-signal areas on T,-weighted scans had decreased in size to resemble the areas previously outlined by Gd-DTPA. This technique provides useful information about the pathogenesis and behavior of MS lesions. NEUROLOGY 199Q40229-235
Enhancement of multiple sclerosis lesions with iodine on CT or gadolinium-DTPA (Gd-DTPA) on magnetic resonance imaging (MRI) is a common observation in patients with relapsing and remitting disease.'-6 It is usually interpreted as being due to an alteration in the blood-brain b a r ~ i e r .Not ~ . ~all lesions enhance at a given time, and the pattern of enhancement varies, sornetimes having a homogeneous appearance, and sometimes a ring-like form.8 Miller et a16 found that "3 of lesions enhancing on an initial scan no longer did so after 5 weeks, yet all of 12 new lesions did. A number of questions arise. Is enhancement a universal feature of new lesions? What is the explanation for the variable appearance of enhancement? What is the natural history of individual lesions? What do the different patterns of enhancement signify physiologically and pathologically? Because answers to these questions are a prerequisite for the effectiveuse of MRI in monitoring treatment, we undertook a study of the natural history of individual lesions, using serial dynamic Gd-DTPAenhanced MRI in patients with clinically definite MS. Methods. Patients. We studied 8 women with clinically definite MS,9 mean age 31 years (range, 15 to 43). All had typical relapsing and remitting disease, mean duration 4.4 years, and 1had recently entered the progressive phase of the disease. Six patients were recruited within 3 weeks of the onset of a clinical relapse.
Fifteen dynamic Gd-DTPA studies were performed; 7 were follow-up studies comprising 4, 2, and 1 repeat dynamic GdDTPA MRIs in 3 patients at intervals from 7 days to 3 months. Additional unenhanced preliminary and follow-up MRIs were performed in 5 patients. Four patients had been treated with corticosteroids during or near to the period of study: 2 patients had completed a 5-day course of 500 mg IV methylprednisolone 3 and 4 days before their 1st Gd-DTPA MRI, and 1commenced a 5-day course on the day of the first Gd-DTPA MRI. The 4th patient was on oral prednisolone 25 mg daily, which was reduced to 15 mg daily by the time of her follow-up scan 14 days later. Imaging. Scanning was performed on a Picker 0.5T superconducting MR imager. All patients had an initial T,weighted MRI (SE,,, Bo, 5-mm contiguous slices) with scanning plane determined by 4 pilots (transverse, coronal, sagittal, and a final check transverse pilot). It was followed by unenhanced T,-weighted MRIs (in early studies SE,,,,, later IRlozo/40/5~ with SEIOZOIIO, all 5-mm contiguous slices) as a baseline, with calculation of T, values for lesions and normalappearing white matter in the later studies. A bolus injection of Gd-DTPA 0.1 to 0.2 mmol/kg over 1minute into previously inserted venous access followed,with the patient remaining in the scanner to ensure precise image registration. Because the patient was not moved, potential errors in measurement of lesion intensity and enhancement introduced by repositioning were avoided. Immediately following completion of GdDTPA injection, serial MRI studies (SE,,, or, IR~020/40/5, in later studies) were performed producing 8 axial images repeated at approximately 4-minute intervals. Attenuation was
From the Multiple Sclerosis NMR Research Group (Drs. Kermode, Tofts, Thompson, Rudge, du Boulay. and McDonald,and Mr. MacManus), Institute of Neurology, and The National Hospitals For Nervous Diseases (Drs. Kermode, Thompson, Rudge, Kendall, Kingsley, Moseley, du Boulay, and McDonald), London, UK. The Multiple SclerosisNMR Research Group is supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland, and also by the Medical Research Council of Great Britain. Received June 1,1989. Accepted for publication in final form July 13, 1989. Address correspondence and reprint requests to Dr. A.G. Kermode, NMR Research Group, Institute of Neurology, Queen Square, London WClN 3BG, UK.
February 1990 NEUROLOGY 40 229
Figure 1. All images are of the same slice in the same patient. T h e patient was not on steroids. (A) Unenhanced T,-weighted MRI (SE20m,6Jshowing confluent high-signal lesions. (B) Corresponding unenhanced TI-weighted MRI (SE5m,4J several minutes later, before Gd-DTPA. Note that lesions are not apparent with this sequence if unenhanced. Arrows point to high signal at the edges of subsequent enhancement shown i n the next image. (C) Enhanced MRI (SE5,,4& 6 minutes after Gd-DTPA showing “honeycomb” enhancement within the lesions. (0) MRI (SE,,o,4J 80 minutes after Gd-DTPA. ( E ) Unenhanced T,-weighted MRI (SEzo,,6J 3 months later showing dramatic shrinkage of lesions, which now resemble the areas outlined 3 months previously by contrast. Note 3 new large lesions. (F) Corresponding enhanced T,-weighted MRI (IR1020,40,5W) 4 minutes after Gd-DTPA showing enhancement i n 2 of these new lesions with enhancement (arrows). (G) T e n minutes after Gd-DTPA (IRlo20,40,5~, once again appearing more uniform than in the early post Gd-DTPA images, T h e 3rd lesion is now visibly enhancing.
set manually. Patient movement was minimized using a flexible guide. The maximum study duration was 384 minutes, with rest breaks, and mean study duration 151 minutes. The time course of intensity changes of 102 lesions before and after contrast 230 NEUROLOGY 40 February 1990
was measured quantitatively using both scanner software and a remote Sun 3 workstation running “Analyze” image analysis software (Biodynamics Group, Mayo Clinic). Intensity (in arbitrary units) was measured a t constant positions within the enhanced region using a “region of interest” depending on
C
A
D
Figure 2. All images are of the same slice in the same patient. (A) Unenhanced T,-weighted initial MRI (SE,mo,60,5-mm slice) showing large confluent high-signal areas. (B) Enhanced TI-weightedMRI (SE,,I,,J 2 minutes after Gd-DTPA injection, showing “ring” lesions within the confluent lesion seen on T,-weighted image. (C) Fifteen minutes after contrast injection (SE,,,4d, the rings now appear more uniformly enhanced. ( 0 ) Five hours later (SEsoOI,,J, there is centrifugal and centripetal spread of contrast, and lower signal in the original rings of enhancement (arrow).
lesion size (between 6 and 56 pixels). This region was kept constant for the analysis of the dynamic scans. The intensity measurements were performed by 1observer (A.G.K.), without reference to intensity values obtained from other studies. T, values were also calculated in later studies. For serial scans, repositioning had been better than f 4 degrees in previous studies,’O and our current method represents a further improvement.
Results. In the initial scans, the areas of enhancement varied in appearance and size, but were often smaller than the area of abnormal signal on the corresponding unenhanced scan (figures1 and 2) and often appeared as rings. In some instances, they had the appearance of multiple confluent enhancing rings forming a “honeycomb” within the abnormal area. Small new enhancing regions developed within the more extensive T,weighted regions of high signal as the regions enlarged, and all enlarging lesions contained areas of enhancement. In the serial scans, there were 11 new lesions known to be less than 5 weeks old. All enhanced, in keeping with the observations of Miller et aL6A further 9 of 13 lesions known to be less than 12 weeks of age also enhanced. Enhancement thus appears to be a consis-
tent feature of new lesions in patients with relapsing and remitting or secondarily progressive MS. Three lesions were seen with Gd-DTPA but not with unenhanced T,-weighted sequences in 2 patients that were not on treatment. One lesion was easily seen 10 days later without enhancement (figure 3), providing evidence that blood-brain barrier breakdown may precede other MRI signs of lesion formation. Serial scans in patients showing extensive areas of abnormal signal on unenhanced scans (eg, figure 1A) often showed the extent of the area of abnormal signal to decrease in size after several months to approach that of the initial area of enhancement (figure 1, C through E). This was seen in both treated and untreated patients. The bolus of Gd-DTPA was given over 1 minute with the patient still in the scanner. Imaging began immediately afterwards, and the 1stset was availableafter 2.3 to 4.1 minutes. In such early scans, multiple enhancing lesions were commonly present (figures 1 through 3). Some small lesions appeared to enhance homogeneously, whereas others showed a ring-like appearance. Comparison of contiguous slices showed that some apFebruary 1990 NEUROLOGY 40 231
Figure 3. All images are of the same slice in the same patient. The patient was not on steroids. (A) Unenhanced T,-weighted MRI (SE,,,J No lesion is visible at arrow. (B) Enhanced MRI (SE,,,,d 3 minutes after Gd-DTPA showing a brightly enhancing lesion. (C) Unenhanced MRI (SEzo,o16& 10 days later. The arrowed lesion is now clearly visible.
parently homogeneously enhancing lesions were in fact part of ring-like structures. Most of the larger lesions had a ring-like structure, although occasionally lesions as large as 10 mm in diameter were homogeneous at this stage. Close inspection of the unenhanced scans showed in some lesions that the position of the initial ring of enhancement corresponded with an area of relatively higher signal (figure 1B). A striking change in the appearance of the lesions was observed in the 16-and 20-minute scans (figure 2C). The majority of lesions now appeared to enhance homogeneously, the original rings having been filled in. Over time, the Gd-DTPA also spread beyond the initial margin of enhancement into the white matter, and after several hours the centers (initially unenhanced) became relatively the brightest regions. This effect was especially noticeable in the largest ring-enhancing lesions. The site of the original “ring” was now of darker intensity than the rest of the lesion (figures 2D and 4B), consistent with diffusion of Gd-DTPA back into the bloodstream as the blood level fell.” Five hours post GdDTPA, the area of enhancement in the white matter often resembled the large confluent lesions seen on T,weighted images (figure 4B). Some ring enhancing lesions followed serially over several weeks showed progressive enlargement corresponding to enlargement on T,-weighted images. Time course of intensity changes. Maximum inten232 NEUROLOGY 40 February 1990
sity of enhancement occurred from 4 to 120 minutes after contrast injection, the great majority of lesions reaching it around the mean time of 29 minutes. Figure 5a shows the plots of the time course of enhancement of 2 of 5 enhancing lesions in a single patient on the same occasion. In a lesion known from serial scans to be less than 2 weeks old (lesion A), peak enhancement was reached at 19 minutes. By contrast, peak enhancement in some other lesions more than 3 weeks old (eg, lesion B) in the same scan was reached after over 30 minutes. Figure 5b shows a plot of the time course of enhancement of lesions in another patient, together with that of the same patient’s choroid plexus, a structure which does not have a blood-tissue barrier.’, The peak intensity in the latter was reached at 4 minutes, which is comparable with the time to peak in the rapidly enhancing lesion. Whether early enhancement will prove to be a consistent feature of new lesions, and delayed enhancement of older lesions, remains to be established with further serial studies. The data, however, shows that in a given patient different lesions show a marked heterogeneity in the blood-brain barrier disturbance. All lesions seen at 3 minutes after contrast injection appeared brighter in subsequent dynamic scans, and none had disappeared by 28 minutes after contrast. Many smaller and uniformly enhancing lesions had disappeared by 80 minutes, with the larger ring lesions remaining bright at 5 hours after contrast injection.
Figure 4. Images of the patient in figure 1 obtained 3 weeks earlier demonstrate the spread of contrast. The patient was not on steroids. (A) Enhanced MRI (SE,oo,4d15 minutes after Gd-DTPA showing multiple ring lesions. (B) MRI (SE,o,14d 384 minutes after GdDTPA. Note that the enhanced region now resembles that in figure lA, and also that the original rings are now of lower intensity.
A
B
The time course of enhancement was similar to that found in enhanced x-ray CT studies in MS.13 The present study was not designed to assess the effects of steroids on enhancement, but 4 patients were scanned (5 dynamic studies) during or within 15days of having such therapy. We therefore compared the observations in the treated and untreated groups. There was no difference in the form of lesions in the 2 groups, and in the dynamic scans the mean time to peak enhancement was 27 minutes in the treated patients compared with 29 minutes in the untreated patients. The difference in the mean was not significant (p = 0.08). In 1 patient during treatment with steroids, 2 new lesions were seen to form, both of which enhanced.
Discussion. The salient findings of this study are that all identifiably new lesions in relapsing and remitting or secondarily progressive MS have a phase of enhancement which may predate other MRI changes. In the majority of enhancing lesions greater than 5 mm in diameter, enhancement 4 minutes after injection was ring-like, but became homogeneous by 16 to 20 minutes; by 5 hours the enhanced region had enlarged and the pattern of intensity within the lesion had changed; the time course of enhancement following each individual injection varied at different stages of the natural history of the lesion. What do the different patterns of enhancement represent in pathologic terms? There is now much evidence that the tissue damage in MS is mediated immunologically.7J4-1~ Hawkins e t all7 have used chronic relapsing experimental allergic encephalomyelitis (CREAE) as a model of immune-mediated demyelination to elucidate the mechanism of enhancement. It was seen only in areas where there was perivascular inflammation histologically. In terminal experiments, when enhancement with Gd-DTPA was followed imm,ediately by injection with blood-brain barrier markers (horseradish peroxidase, lanthanum nitrate, gadolinium nitrate), there was always leakage into the perivascular and adjacent neural extracellular
spaces. Tight junctions between the endothelial cells remained intact. However, the number of endothelial cytoplasmic vesicles containing blood-brain barrier marker increased. These observations led to the conclusion that a n increase in vesicular transport of gadolinium plays a significant part in the breakdown of the blood-brain barrier in CREAE.17 Demyelination was also present in the lesions, but since noninflammatory demyelination is unaccompanied by changes in blood-brain barrier permeability,ls the necessary condition for the development of enhancement is inflammation. From the similarity in morphologic and functional changes between CREAEl9and MS, we conclude that enhancement in the human disease reflects active inflammation. The mechanism -of breakdown of the blood-brain barrier in MS is probably similar, and evidence of increased numbers of endothelial vesicles at postmortem in MS has been reported.20 In the active lesion of CREAE there is an increase in permeability not only to the relatively small molecule Gd-DTPA (molecular weight, 550)21but to the much larger molecules Gd-albumin and Gd-albumin-IgG.17 The presence at postmortem of fibrin in the perivascular space in MS in active lesions is evidence for a similar generalized increase in permeability in the human disease.15 This observation is in keeping with ours that in some lesions maximum intensity of enhancement is reached as rapidly as in the choroid plexus where there is no significant blood-tissue barrier.12The longer time to peak enhancement in older lesions suggests that the restoration of impermeability is gradual. The cellular mechanism responsible for these changes is still obscure. What do the different patterns of enhancement in MS represent? If, as we have argued, enhancement reflects active inflammation, the small homogeneous lesions could be accounted for by the small areas of perivascular inflammation at postmortem either at the edges of established lesions (Dawson’s fingers) or in areas of otherwise normal-appearing white matter. February 1990 NEUROLOGY 40 233
Lesion A Lesion B
0
Time (mins post Gd-DTPA)
Lesion A Lesion 5 Choroid
2oo!
20
40
60
80
100
Time (mins post Gd-DTPA)
Figure 5. (a) T i m e course of enhancement in 1 dynamic study of a uniformly enhancing lesion known from serial scans to be less than 2 weeks old (Lesion A) versus a lesion more than 3 weeks old (Lesion B). Intensity is in arbitrary units. T h e patient was not o n steroids. (b) Time course of enhancement in another dynamic study showing a rapidly enhancing lesion (Lesion A) and a typical, more slowly enhancing lesion (Lesion B). T h e enhancement of choroid plexus is plotted for comparison. Intensity is in arbitrary units. T h e patient was not o n steroids.
Large ring-like lesions probably represent acute inflammation at the edge of chronic demyelinating lesions, as has been observed pathologically.22Histologically, such lesions also have myelin breakdown products in this region. The areas of ring enhancement in some lesions occurred at the site of rings of relatively higher signal in the unenhanced T,-weighted MRI (figure l),known in some of our cases to be due to decreased T,. Such high signal could be produced by myelin breakdown products, their increased mobility and surface area relative to intact myelin enhancing the relaxation rate.23 Why do the ring lesions enhance uniformly, or “fill in,” 10 to 20 minutes after contrast? One possibility is that the blood-brain barrier permeability in the center may be lower than at the periphery, resulting in a slower rise in concentration of Gd-DTPA centrally. Alternatively, the center may have an intact blood-brain barrier and the Gd-DTPA diffuses inward from the enhancing margin. Both processes may well contribute. A quantitative model of enhancement based on com234 NEUROLOGY 40 February 1990
partmental analysis currently being developedz4may help to decide the relative contribution of the 2 mechanisms. The increase in area of enhancement over several hours to resemble the areas seen on T,-weighted unenhanced scans, accompanied by progressively less distinct outlines, suggests that diffusion of gadolinium is taking place into the extracellular space, a view which is compatible with the hypothesis that edema extends beyond the region with active blood-brain barrier breakdown. Some lesions on serial scanning showed renewed enhancement, the diameter of the new “rings” being larger on the 2nd occasion than the lst, thus providing direct evidence for the conjecture that chronic lesions can extend by centrifugal expansion.22 Re-enhancement was sometimes seen within an apparently homogeneous lesion. Whether it was due to fresh damage to previously affected vessels or to new damage to intact vessels in a patch of normal white matter within an irregularly shaped lesion is uncertain. We found similar appearances and times to peak enhancement in both untreated and steroid-treated patients, and only 5 of 15 dynamic scans were performed within 7 days of steroids. Treatment with steroids cannot account for the marked heterogeneity of bloodbrain barrier disturbances or observed imaging appearances. During high-dose IV methylprednisolone, new lesions formed; similar observations have been reported p r e v i o ~ s l yChanges .~~ in T, and T, occur followinghighdose IV methylpredni~olone,~~ and it is possible that a systematic quantitative study might reveal changes in blood-brain barrier permeability. An investigation to define the relationship of the differing blood-brain barrier disturbances to clinical relapse is in progress. Isaac et alZ6observed that acute lesions wane in size after an earlier waxing, reaching a minimum after about 3 months. Our observation that such shrinking lesions often have a smaller enhancing center in the early stages suggests the larger areas represent edema, an interpretation which is supported by previous observations of “shrinking” lesions on CT.4 Gd-DTPA images may therefore be a more reliable indicator of true lesion size than T,-weighted images in the acute phase. Studies of experimental cold lesions, and of chronic MS lesions, indicate that abnormal signal in residual lesions may arise from varying contribution of increased extracellular fluid and g l i o ~ i sIt. is ~ unlikely ~ ~ ~ ~ that the latter alone can account for the high signal seen in many lesions. Inflammatory cells may also make a contribution in the early chronic phase. Our observations have implications for the use of MRI in monitoring treatment. The very striking changes in apparent size of some lesions means that simply measuring the area (or volume) of zones of abnormal signal may be misleading. Other quantitative monitoring approaches, such as T, and T, relaxation times within lesions, are only indirectly related to lesion pathology and vary with field strength. Measurement of blood-brain barrier permeability provides physiologic data which are more directly related to lesion activity, reflecting, we have argued, inflammation. It may be
helpful in both short- and long-term monitoring of treatment for the individual relapse, and of treatment designed to modify the course of the disease.
Acknowledgments Gadolinium-DTPA was provided by Schering AG. We are grateful to R. Robb, Biodynamics Group, The Mayo Clinic, for providing Analyze image processing software.
References 1. Harding AE, Radue EW, Whiteley AM. Contrast-enhanced lesions on computerised tomography in multiple sclerosis. J Neurol Neurosurg Psychiatry 1978;41:754-758. 2. Grossman RI, Gonzalez-Scarano F, Atlas SW, Galetta S, Silberberg DH. Multiple sclerosis: gadolinium enhancement in MR imaging. Radiology 1986;161:721-725. 3. Vinuela FV, Fox AJ, Debrun GM, Feasby TE, Ebers GC. New perspectives in computed tomography of multiple sclerosis. Am J Roentgen01 1982;139:123-127. 4.Aita JF. Cranial CT as an aid in diagnosis of multiple sclerosis. Appl Radiology 1981;10:33-37. 5. Sears ES, Hayman LA, Bigelow R. Emerging patterns of lesion activity duringmultiple sclerosis exacerbations. Trans Am Neurol ASSOC1981;106:259-261. 6. Miller DH, Rudge P, Johnson G, et al. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 1986111~927-939. 7. Lightman S, McDonald WI, Bird AC, e t al. Retinal venous sheathing in optic neuritis: its significance for the development of multiple sclerosis. Brain 1987;110:405-414. 8. Kermode AG, Tofts PS, MacManus DG, et al. The early lesion of multiple sclerosis. Lancet 1988;2:1203-1204. 9. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231. 10. Ormerod IEC, Miller DH, McDonald WI, et al. The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions: a quantitative study. Brain 1987;110:1579-1616. 11. Weinmann HJ, Laniado M, Mutzel W. Pharmacokinetics of GdDTPA/dimeglumine after intravenous injection into healthy volunteers. Physiol Chem Phys Med NMR 1984;16:167-172. 12. Kilgore DP, Breger RK, Daniels DL, Pojunas KW, Williams AL, Haughton AM. Cranial tissues: normal MR appearance after intravenous injection of Gd-DTPA. Radiology 1986;160:757-761.
13. Sears ES, McCammon A, Bigelow R, Hayman LA. Maximizing the harvest of contrast enhancing lesions in multiple sclerosis. Neurology 1982;32:815-820. 14. Silberberg DH. Pathogenesis of demyelination. In: McDonald WI, Silberberg DH, eds. Multiple sclerosis. Boston: Butterworths, 1986~99-111. 15. Adams CWM, Poston RN, Buk SJ, Sidhu YS, Vipond H. Inflamm a t o r y vasculitis in multiple sclerosis. J Neurol Sci 1985;69:269-283. 16. McFarlin D, McFarland H. Multiple Sclerosis. N Engl J Med 1982;307:1183-1188, 1246-1251. 17. Hawkins CP, Munro MG, Mackenzie F. Duration and selectivity of blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis studied using gadolinium-DTPA and protein markers. Brain (in press). 18. Lumsden CE. The neuropathology of multiple sclerosis. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, vol9. Amsterdam: North Holland, 1970:217-309. 19. Lassman H. Comparative neuropathology of chronic relapsing experimental allergic encephalomyelitis and multiple sclerosis. Berlin: Springer-Verlag, 1983. 20. Brown WJ. The capillaries in acute and subacute multiple sclerosis plaques: a morphometric analysis. Neurology 19762889-92. 21. Gadian DG, Payne JA, Bryant DJ, Young IR, Carr DH, Bydder GM. Gadolinium-DTPA as a contrast agent in MR imaging: theoretical projections and practical observations. J Comput Assist Tomogr 1985;9:242-251. 22. Prineas JW, Connel F. The fine structure of chronically active multiple sclerosis plaques. Neurology 1978;28(Suppl):68-75. 23. Kermode AG, Tofts PS, MacManus DG, McDonald WI. Shortened T, a t the edge of multiple sclerosis lesions. Magn Reson Imaging 1989;7(Suppl 1):168. 24. Tofts PS, Kermode AG. Measurement of blood-brain barrier permeability using Gd-DTPA scanning. Magn Reson Imaging 1989;7(Suppl1):150. 25. Kesselring J , Miller DH, MacManus DG, et al. Quantitative magnetic resonance imaging in multiple sclerosis: the effect of high dose intravenous methylprednisolone. J Neurol Neurosurg Psychiatry 1989;52:1-17. 26. Isaac C, Li DKB, Genton M, et al. Multiple sclerosis: a serial study using MRI in relapsing patients. Neurology 198&38:1511-1515. 27. Barnes D,McDonald WI, Johnson G, Tofts PS, Landon DN. Quantitative nuclear magnetic resonance imaging; characterisation of experimental cerebral oedema. J Neurol Neurosurg Psychiatry 1987;50:125-133. 28. Barnes D, McDonald WI, Landon DN, Johnson G. Characterisation of experimental gliosis by quantitative nuclear magnetic resonance imaging. Brain 1988;111:83-94.
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Heterogeneity of blood−brain barrier changes in multiple sclerosis: An MRI study with gadolinium−DTPA enhancement A. G. Kermode, P. S. Tofts, A. J. Thompson, et al. Neurology 1990;40;229 DOI 10.1212/WNL.40.2.229 This information is current as of February 1, 1990 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1990 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Enhancement of multiple sclerosis lesions with iodine on CT or gadolinium-DTPA (Gd-DTPA) on magnetic resonance imaging (MRI) is a common observation in patients with relapsing and remitting disease.'-6 It is usually interpreted as being due to an alteration in the blood-brain b a r ~ i e r .Not ~ . ~all lesions enhance at a given time, and the pattern of enhancement varies, sornetimes having a homogeneous appearance, and sometimes a ring-like form.8 Miller et a16 found that "3 of lesions enhancing on an initial scan no longer did so after 5 weeks, yet all of 12 new lesions did. A number of questions arise. Is enhancement a universal feature of new lesions? What is the explanation for the variable appearance of enhancement? What is the natural history of individual lesions? What do the different patterns of enhancement signify physiologically and pathologically? Because answers to these questions are a prerequisite for the effectiveuse of MRI in monitoring treatment, we undertook a study of the natural history of individual lesions, using serial dynamic Gd-DTPAenhanced MRI in patients with clinically definite MS. Methods. Patients. We studied 8 women with clinically definite MS,9 mean age 31 years (range, 15 to 43). All had typical relapsing and remitting disease, mean duration 4.4 years, and 1had recently entered the progressive phase of the disease. Six patients were recruited within 3 weeks of the onset of a clinical relapse.
Fifteen dynamic Gd-DTPA studies were performed; 7 were follow-up studies comprising 4, 2, and 1 repeat dynamic GdDTPA MRIs in 3 patients at intervals from 7 days to 3 months. Additional unenhanced preliminary and follow-up MRIs were performed in 5 patients. Four patients had been treated with corticosteroids during or near to the period of study: 2 patients had completed a 5-day course of 500 mg IV methylprednisolone 3 and 4 days before their 1st Gd-DTPA MRI, and 1commenced a 5-day course on the day of the first Gd-DTPA MRI. The 4th patient was on oral prednisolone 25 mg daily, which was reduced to 15 mg daily by the time of her follow-up scan 14 days later. Imaging. Scanning was performed on a Picker 0.5T superconducting MR imager. All patients had an initial T,weighted MRI (SE,,, Bo, 5-mm contiguous slices) with scanning plane determined by 4 pilots (transverse, coronal, sagittal, and a final check transverse pilot). It was followed by unenhanced T,-weighted MRIs (in early studies SE,,,,, later IRlozo/40/5~ with SEIOZOIIO, all 5-mm contiguous slices) as a baseline, with calculation of T, values for lesions and normalappearing white matter in the later studies. A bolus injection of Gd-DTPA 0.1 to 0.2 mmol/kg over 1minute into previously inserted venous access followed,with the patient remaining in the scanner to ensure precise image registration. Because the patient was not moved, potential errors in measurement of lesion intensity and enhancement introduced by repositioning were avoided. Immediately following completion of GdDTPA injection, serial MRI studies (SE,,, or, IR~020/40/5, in later studies) were performed producing 8 axial images repeated at approximately 4-minute intervals. Attenuation was
From the Multiple Sclerosis NMR Research Group (Drs. Kermode, Tofts, Thompson, Rudge, du Boulay. and McDonald,and Mr. MacManus), Institute of Neurology, and The National Hospitals For Nervous Diseases (Drs. Kermode, Thompson, Rudge, Kendall, Kingsley, Moseley, du Boulay, and McDonald), London, UK. The Multiple SclerosisNMR Research Group is supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland, and also by the Medical Research Council of Great Britain. Received June 1,1989. Accepted for publication in final form July 13, 1989. Address correspondence and reprint requests to Dr. A.G. Kermode, NMR Research Group, Institute of Neurology, Queen Square, London WClN 3BG, UK.
February 1990 NEUROLOGY 40 229
Figure 1. All images are of the same slice in the same patient. T h e patient was not on steroids. (A) Unenhanced T,-weighted MRI (SE20m,6Jshowing confluent high-signal lesions. (B) Corresponding unenhanced TI-weighted MRI (SE5m,4J several minutes later, before Gd-DTPA. Note that lesions are not apparent with this sequence if unenhanced. Arrows point to high signal at the edges of subsequent enhancement shown i n the next image. (C) Enhanced MRI (SE5,,4& 6 minutes after Gd-DTPA showing “honeycomb” enhancement within the lesions. (0) MRI (SE,,o,4J 80 minutes after Gd-DTPA. ( E ) Unenhanced T,-weighted MRI (SEzo,,6J 3 months later showing dramatic shrinkage of lesions, which now resemble the areas outlined 3 months previously by contrast. Note 3 new large lesions. (F) Corresponding enhanced T,-weighted MRI (IR1020,40,5W) 4 minutes after Gd-DTPA showing enhancement i n 2 of these new lesions with enhancement (arrows). (G) T e n minutes after Gd-DTPA (IRlo20,40,5~, once again appearing more uniform than in the early post Gd-DTPA images, T h e 3rd lesion is now visibly enhancing.
set manually. Patient movement was minimized using a flexible guide. The maximum study duration was 384 minutes, with rest breaks, and mean study duration 151 minutes. The time course of intensity changes of 102 lesions before and after contrast 230 NEUROLOGY 40 February 1990
was measured quantitatively using both scanner software and a remote Sun 3 workstation running “Analyze” image analysis software (Biodynamics Group, Mayo Clinic). Intensity (in arbitrary units) was measured a t constant positions within the enhanced region using a “region of interest” depending on
C
A
D
Figure 2. All images are of the same slice in the same patient. (A) Unenhanced T,-weighted initial MRI (SE,mo,60,5-mm slice) showing large confluent high-signal areas. (B) Enhanced TI-weightedMRI (SE,,I,,J 2 minutes after Gd-DTPA injection, showing “ring” lesions within the confluent lesion seen on T,-weighted image. (C) Fifteen minutes after contrast injection (SE,,,4d, the rings now appear more uniformly enhanced. ( 0 ) Five hours later (SEsoOI,,J, there is centrifugal and centripetal spread of contrast, and lower signal in the original rings of enhancement (arrow).
lesion size (between 6 and 56 pixels). This region was kept constant for the analysis of the dynamic scans. The intensity measurements were performed by 1observer (A.G.K.), without reference to intensity values obtained from other studies. T, values were also calculated in later studies. For serial scans, repositioning had been better than f 4 degrees in previous studies,’O and our current method represents a further improvement.
Results. In the initial scans, the areas of enhancement varied in appearance and size, but were often smaller than the area of abnormal signal on the corresponding unenhanced scan (figures1 and 2) and often appeared as rings. In some instances, they had the appearance of multiple confluent enhancing rings forming a “honeycomb” within the abnormal area. Small new enhancing regions developed within the more extensive T,weighted regions of high signal as the regions enlarged, and all enlarging lesions contained areas of enhancement. In the serial scans, there were 11 new lesions known to be less than 5 weeks old. All enhanced, in keeping with the observations of Miller et aL6A further 9 of 13 lesions known to be less than 12 weeks of age also enhanced. Enhancement thus appears to be a consis-
tent feature of new lesions in patients with relapsing and remitting or secondarily progressive MS. Three lesions were seen with Gd-DTPA but not with unenhanced T,-weighted sequences in 2 patients that were not on treatment. One lesion was easily seen 10 days later without enhancement (figure 3), providing evidence that blood-brain barrier breakdown may precede other MRI signs of lesion formation. Serial scans in patients showing extensive areas of abnormal signal on unenhanced scans (eg, figure 1A) often showed the extent of the area of abnormal signal to decrease in size after several months to approach that of the initial area of enhancement (figure 1, C through E). This was seen in both treated and untreated patients. The bolus of Gd-DTPA was given over 1 minute with the patient still in the scanner. Imaging began immediately afterwards, and the 1stset was availableafter 2.3 to 4.1 minutes. In such early scans, multiple enhancing lesions were commonly present (figures 1 through 3). Some small lesions appeared to enhance homogeneously, whereas others showed a ring-like appearance. Comparison of contiguous slices showed that some apFebruary 1990 NEUROLOGY 40 231
Figure 3. All images are of the same slice in the same patient. The patient was not on steroids. (A) Unenhanced T,-weighted MRI (SE,,,J No lesion is visible at arrow. (B) Enhanced MRI (SE,,,,d 3 minutes after Gd-DTPA showing a brightly enhancing lesion. (C) Unenhanced MRI (SEzo,o16& 10 days later. The arrowed lesion is now clearly visible.
parently homogeneously enhancing lesions were in fact part of ring-like structures. Most of the larger lesions had a ring-like structure, although occasionally lesions as large as 10 mm in diameter were homogeneous at this stage. Close inspection of the unenhanced scans showed in some lesions that the position of the initial ring of enhancement corresponded with an area of relatively higher signal (figure 1B). A striking change in the appearance of the lesions was observed in the 16-and 20-minute scans (figure 2C). The majority of lesions now appeared to enhance homogeneously, the original rings having been filled in. Over time, the Gd-DTPA also spread beyond the initial margin of enhancement into the white matter, and after several hours the centers (initially unenhanced) became relatively the brightest regions. This effect was especially noticeable in the largest ring-enhancing lesions. The site of the original “ring” was now of darker intensity than the rest of the lesion (figures 2D and 4B), consistent with diffusion of Gd-DTPA back into the bloodstream as the blood level fell.” Five hours post GdDTPA, the area of enhancement in the white matter often resembled the large confluent lesions seen on T,weighted images (figure 4B). Some ring enhancing lesions followed serially over several weeks showed progressive enlargement corresponding to enlargement on T,-weighted images. Time course of intensity changes. Maximum inten232 NEUROLOGY 40 February 1990
sity of enhancement occurred from 4 to 120 minutes after contrast injection, the great majority of lesions reaching it around the mean time of 29 minutes. Figure 5a shows the plots of the time course of enhancement of 2 of 5 enhancing lesions in a single patient on the same occasion. In a lesion known from serial scans to be less than 2 weeks old (lesion A), peak enhancement was reached at 19 minutes. By contrast, peak enhancement in some other lesions more than 3 weeks old (eg, lesion B) in the same scan was reached after over 30 minutes. Figure 5b shows a plot of the time course of enhancement of lesions in another patient, together with that of the same patient’s choroid plexus, a structure which does not have a blood-tissue barrier.’, The peak intensity in the latter was reached at 4 minutes, which is comparable with the time to peak in the rapidly enhancing lesion. Whether early enhancement will prove to be a consistent feature of new lesions, and delayed enhancement of older lesions, remains to be established with further serial studies. The data, however, shows that in a given patient different lesions show a marked heterogeneity in the blood-brain barrier disturbance. All lesions seen at 3 minutes after contrast injection appeared brighter in subsequent dynamic scans, and none had disappeared by 28 minutes after contrast. Many smaller and uniformly enhancing lesions had disappeared by 80 minutes, with the larger ring lesions remaining bright at 5 hours after contrast injection.
Figure 4. Images of the patient in figure 1 obtained 3 weeks earlier demonstrate the spread of contrast. The patient was not on steroids. (A) Enhanced MRI (SE,oo,4d15 minutes after Gd-DTPA showing multiple ring lesions. (B) MRI (SE,o,14d 384 minutes after GdDTPA. Note that the enhanced region now resembles that in figure lA, and also that the original rings are now of lower intensity.
A
B
The time course of enhancement was similar to that found in enhanced x-ray CT studies in MS.13 The present study was not designed to assess the effects of steroids on enhancement, but 4 patients were scanned (5 dynamic studies) during or within 15days of having such therapy. We therefore compared the observations in the treated and untreated groups. There was no difference in the form of lesions in the 2 groups, and in the dynamic scans the mean time to peak enhancement was 27 minutes in the treated patients compared with 29 minutes in the untreated patients. The difference in the mean was not significant (p = 0.08). In 1 patient during treatment with steroids, 2 new lesions were seen to form, both of which enhanced.
Discussion. The salient findings of this study are that all identifiably new lesions in relapsing and remitting or secondarily progressive MS have a phase of enhancement which may predate other MRI changes. In the majority of enhancing lesions greater than 5 mm in diameter, enhancement 4 minutes after injection was ring-like, but became homogeneous by 16 to 20 minutes; by 5 hours the enhanced region had enlarged and the pattern of intensity within the lesion had changed; the time course of enhancement following each individual injection varied at different stages of the natural history of the lesion. What do the different patterns of enhancement represent in pathologic terms? There is now much evidence that the tissue damage in MS is mediated immunologically.7J4-1~ Hawkins e t all7 have used chronic relapsing experimental allergic encephalomyelitis (CREAE) as a model of immune-mediated demyelination to elucidate the mechanism of enhancement. It was seen only in areas where there was perivascular inflammation histologically. In terminal experiments, when enhancement with Gd-DTPA was followed imm,ediately by injection with blood-brain barrier markers (horseradish peroxidase, lanthanum nitrate, gadolinium nitrate), there was always leakage into the perivascular and adjacent neural extracellular
spaces. Tight junctions between the endothelial cells remained intact. However, the number of endothelial cytoplasmic vesicles containing blood-brain barrier marker increased. These observations led to the conclusion that a n increase in vesicular transport of gadolinium plays a significant part in the breakdown of the blood-brain barrier in CREAE.17 Demyelination was also present in the lesions, but since noninflammatory demyelination is unaccompanied by changes in blood-brain barrier permeability,ls the necessary condition for the development of enhancement is inflammation. From the similarity in morphologic and functional changes between CREAEl9and MS, we conclude that enhancement in the human disease reflects active inflammation. The mechanism -of breakdown of the blood-brain barrier in MS is probably similar, and evidence of increased numbers of endothelial vesicles at postmortem in MS has been reported.20 In the active lesion of CREAE there is an increase in permeability not only to the relatively small molecule Gd-DTPA (molecular weight, 550)21but to the much larger molecules Gd-albumin and Gd-albumin-IgG.17 The presence at postmortem of fibrin in the perivascular space in MS in active lesions is evidence for a similar generalized increase in permeability in the human disease.15 This observation is in keeping with ours that in some lesions maximum intensity of enhancement is reached as rapidly as in the choroid plexus where there is no significant blood-tissue barrier.12The longer time to peak enhancement in older lesions suggests that the restoration of impermeability is gradual. The cellular mechanism responsible for these changes is still obscure. What do the different patterns of enhancement in MS represent? If, as we have argued, enhancement reflects active inflammation, the small homogeneous lesions could be accounted for by the small areas of perivascular inflammation at postmortem either at the edges of established lesions (Dawson’s fingers) or in areas of otherwise normal-appearing white matter. February 1990 NEUROLOGY 40 233
Lesion A Lesion B
0
Time (mins post Gd-DTPA)
Lesion A Lesion 5 Choroid
2oo!
20
40
60
80
100
Time (mins post Gd-DTPA)
Figure 5. (a) T i m e course of enhancement in 1 dynamic study of a uniformly enhancing lesion known from serial scans to be less than 2 weeks old (Lesion A) versus a lesion more than 3 weeks old (Lesion B). Intensity is in arbitrary units. T h e patient was not o n steroids. (b) Time course of enhancement in another dynamic study showing a rapidly enhancing lesion (Lesion A) and a typical, more slowly enhancing lesion (Lesion B). T h e enhancement of choroid plexus is plotted for comparison. Intensity is in arbitrary units. T h e patient was not o n steroids.
Large ring-like lesions probably represent acute inflammation at the edge of chronic demyelinating lesions, as has been observed pathologically.22Histologically, such lesions also have myelin breakdown products in this region. The areas of ring enhancement in some lesions occurred at the site of rings of relatively higher signal in the unenhanced T,-weighted MRI (figure l),known in some of our cases to be due to decreased T,. Such high signal could be produced by myelin breakdown products, their increased mobility and surface area relative to intact myelin enhancing the relaxation rate.23 Why do the ring lesions enhance uniformly, or “fill in,” 10 to 20 minutes after contrast? One possibility is that the blood-brain barrier permeability in the center may be lower than at the periphery, resulting in a slower rise in concentration of Gd-DTPA centrally. Alternatively, the center may have an intact blood-brain barrier and the Gd-DTPA diffuses inward from the enhancing margin. Both processes may well contribute. A quantitative model of enhancement based on com234 NEUROLOGY 40 February 1990
partmental analysis currently being developedz4may help to decide the relative contribution of the 2 mechanisms. The increase in area of enhancement over several hours to resemble the areas seen on T,-weighted unenhanced scans, accompanied by progressively less distinct outlines, suggests that diffusion of gadolinium is taking place into the extracellular space, a view which is compatible with the hypothesis that edema extends beyond the region with active blood-brain barrier breakdown. Some lesions on serial scanning showed renewed enhancement, the diameter of the new “rings” being larger on the 2nd occasion than the lst, thus providing direct evidence for the conjecture that chronic lesions can extend by centrifugal expansion.22 Re-enhancement was sometimes seen within an apparently homogeneous lesion. Whether it was due to fresh damage to previously affected vessels or to new damage to intact vessels in a patch of normal white matter within an irregularly shaped lesion is uncertain. We found similar appearances and times to peak enhancement in both untreated and steroid-treated patients, and only 5 of 15 dynamic scans were performed within 7 days of steroids. Treatment with steroids cannot account for the marked heterogeneity of bloodbrain barrier disturbances or observed imaging appearances. During high-dose IV methylprednisolone, new lesions formed; similar observations have been reported p r e v i o ~ s l yChanges .~~ in T, and T, occur followinghighdose IV methylpredni~olone,~~ and it is possible that a systematic quantitative study might reveal changes in blood-brain barrier permeability. An investigation to define the relationship of the differing blood-brain barrier disturbances to clinical relapse is in progress. Isaac et alZ6observed that acute lesions wane in size after an earlier waxing, reaching a minimum after about 3 months. Our observation that such shrinking lesions often have a smaller enhancing center in the early stages suggests the larger areas represent edema, an interpretation which is supported by previous observations of “shrinking” lesions on CT.4 Gd-DTPA images may therefore be a more reliable indicator of true lesion size than T,-weighted images in the acute phase. Studies of experimental cold lesions, and of chronic MS lesions, indicate that abnormal signal in residual lesions may arise from varying contribution of increased extracellular fluid and g l i o ~ i sIt. is ~ unlikely ~ ~ ~ ~ that the latter alone can account for the high signal seen in many lesions. Inflammatory cells may also make a contribution in the early chronic phase. Our observations have implications for the use of MRI in monitoring treatment. The very striking changes in apparent size of some lesions means that simply measuring the area (or volume) of zones of abnormal signal may be misleading. Other quantitative monitoring approaches, such as T, and T, relaxation times within lesions, are only indirectly related to lesion pathology and vary with field strength. Measurement of blood-brain barrier permeability provides physiologic data which are more directly related to lesion activity, reflecting, we have argued, inflammation. It may be
helpful in both short- and long-term monitoring of treatment for the individual relapse, and of treatment designed to modify the course of the disease.
Acknowledgments Gadolinium-DTPA was provided by Schering AG. We are grateful to R. Robb, Biodynamics Group, The Mayo Clinic, for providing Analyze image processing software.
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Heterogeneity of blood−brain barrier changes in multiple sclerosis: An MRI study with gadolinium−DTPA enhancement A. G. Kermode, P. S. Tofts, A. J. Thompson, et al. Neurology 1990;40;229 DOI 10.1212/WNL.40.2.229 This information is current as of February 1, 1990 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1990 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
